To clarify the joint effects of environmental and genetic factors in the etiology of breast cancer, the NIEHS Sister Study will prospectively study of 50,000 sisters of women who have had breast cancer. Such sisters have about twice the risk of developing breast cancer as other women. The frequency of any relevant genes and shared risk factors will also be higher, enhancing the statistical power of the study to detect risks. Sisters are expected to be highly motivated and response rates and compliance over time are expected to be high. Thus, studying sisters will enhance our ability to understand the interplay of genes and environment in breast cancer risk and to identify potentially preventable risk factors. The prospective design will allow us assess exposures before the onset of disease thus avoiding biases common to retrospective studies and aiding in causal interpretation. The study will create a framework from which to test new hypotheses as they emerge. Recruitment strategies are designed to maximize inclusion of minorities and high-risk women. Data on potential risk factors and current health status are collected using computer assisted telephone interviews and mail questionnaires. Blood, urine, and environmental samples are collected and banked for future use in nested studies of women who develop breast cancer (or other diseases) and a sample of those who don't. The cohort will be followed prospectively for 10 or more years. Address changes, vital status, and major health changes will be updated annually. Detailed health and exposure updates will be collected at 2-year intervals. Medical records and tumor tissue (for breast cancer cases)will be retrieved for those who develop cancer or other conditions of interest. 1500 new cases of breast cancer are expected to occur in the cohort after five years. Analyses will assess the independent and combined effects of environmental exposures and genetic polymorphisms that affect estrogen metabolism, DNA repair, and response to specific environmental exposures. Future analyses will focus on known and potential risk factors (e.g. smoking, occupational exposures, alcohol, diet, obesity) and include measurement of phthalates, phytoestrogens, and metals in blood and urine, insulin, growth factors, vitamins and nutrients, and genes. The cohort will be used to also study risk for other diseases (e.g. heart disease, osteoporosis, other hormonal cancers, and autoimmune diseases) as well as explore genetic and environmental effects on prognosis. A pilot phase began August 2003 involving women from 4 metropolitan areas of the US selected for their geographic and ethnic diversity in order to assess a range of recruitment strategies and plan for a larger scale national effort. The study began recruiting nationally in October 2004. To date more than 24,000 women have enrolled in the study and 14,000 have completed all baseline activities. An annual update form was mailed to all pilot participants; the response rate was 97%. The biennial follow-up questionnaire is now being drafted as is a special focus questionnaire devoted to stress and social support. All study materials have been translated into Spanish in anticipation of the National Spanish-language launch in late September 2005.